Coated tablet formulations and uses thereof

a technology of coated tablets and formulations, applied in the field of oral pharmaceutical formulations, can solve the problems of chemical degradation and stability, inability to develop a neratinib maleate formulation comprising a capsule or tablet of higher strength, and inability to meet the requirements of pharmaceutical operations, so as to achieve the effect of improving processing characteristics and maintaining acceptable pharmokinetic properties

Active Publication Date: 2011-05-12
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The present invention also provides methods of preparing stable, pharmaceutically acceptable neratinib-maleate formulations for oral administration comprising components described above and herein, which allow for improved processing characteristics while maintaining acceptable pharmokinetic properties.

Problems solved by technology

As a consequence of cohesiveness, neratinib maleate powder does not lend itself easily to pharmaceutical operations such as mixing, flow or fluidization especially when it constitutes a high proportion in a composition.
Due to these limitations, it was not possible to develop a neratinib maleate formulation comprising a capsule or tablet of higher strength employing a direct compression or roller compaction processes successfully.
A formulation using a conventional wet granulation method led to chemical degradation and stability issues.

Method used

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  • Coated tablet formulations and uses thereof
  • Coated tablet formulations and uses thereof
  • Coated tablet formulations and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Coated Tablets of a Neratinib Maleate Formulation by Fluid Bed Wet Granulation Process

[0041]A pharmaceutically acceptable formulation of neratinib mealate is prepared: a granulation comprising intragranular components (a) 10-70 weight percent of neratinib maleate; (b) 15-65 weight percent of mannitol and microcrystalline cellulose; (c) 0.5-8 weight percent of crospovidone or crosscarmellose sodium; (d) 0.2-8 weight percent of colloidal silicon dioxide, and (e) 5-15 weight percent of povidone. The granulation is combined with extragranular components (f) 4-25 weight percent of microcrystalline cellulose; (g) 1-8 weight percent of crospovidone and (h) 0.5-3 weight percent of magnesium stearate, and then compressed into tablets or dry-filled into capsules. This and certain preferred ranges of materials are shown below in Table 1.

TABLE 1Weight %Weight %ComponentWeight %rangerangeIntra-granular componentsHKI-272 Maleate, anhydrous4120-5010-70Mannitol15-65Microcrystalline c...

example 2

Unit Dosage Forms of an Exemplary Neratinib Maleate Formulation

[0052]Using the fluid bed process described in Example 1, different unit dosages of neratinib maleate were prepared from an exemplary formulation, as summarized in Table 2.

TABLE 2Granulation40 mg80 mg240 mgIngredientFunctionwt / wt (%)mg / tabletMg / tabletmg / tabletIntragranular ComponentsHKI-272 MaleateaActive35.0040.0080.00240.00Mannitol (PearlitolDiluent38.9444.5089.01267.02200 SD)MicrocrystallineDiluent10.5612.0724.1472.41(Avicel PH 101)CrospovidoneDisintegrant3.003.436.8620.57Povidone USP / K-25Surface5.005.7111.4334.29ModifyingAgentColloidal SiO2Glidant2.002.294.5713.71Extragranular ComponentsAvicel PH 101Diluent1.501.713.4310.29CrospovidoneDisintegrant2.002.294.5713.71Mg StearateLubricant2.002.294.5713.71Total Wt.100.00114.29228.57685.71Film Coating:Opadry IIFilm Coat—3.429——(85F15443) Red(3%)Opadry IIFilm Coat——6.86—(85F92177) Yellow(3%)Opadry IIFilm Coat———20.57(85F94211) Pink(3%)Total Tablet Wt—117.714235.43706.28aWeig...

example 3

Coated Tablets of Targeted Release Neratinib Maleate Manufactured by Spraying Povidone on Intragranular Components in a Fluid Bed

[0053]An exemplary targeted release (TR) neratinib maleate formulation is summarized in Table 3.

TABLE 340 mg240 mgTabletTabletIngredient% wt / wt(mg)(mg)FunctionIntragranular ComponentsHKI-272 Maleate, anhydrous35.0040.0240.00ActiveMannitol38.2543.79262.72FillerMicrocrystalline cellulose,12.7514.5086.99FillerCrospovidone3.003.4320.57DisintegrantPovidone5.005.7134.29SurfaceModifyingAgentColloidal Silicon Dioxide0.500.573.43GlidantExtra-granular ComponentsMicrocrystalline cellulose3.003.4320.57FillerCrospovidone2.002.2913.71DisintegrantMagnesium stearate0.500.573.43LubricantTotal (Core Tablet)100.00114.29685.71Film coat:Opadry ®3.4320.57Film coat

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Abstract

The present invention provides coated tablet formulations comprising neratinib maleate, and improved methods for making such coated tablets.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Application No. 61 / 259,403, filed Nov. 9, 2009, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to oral pharmaceutical formulations of neratinib provided in the form of coated tablets prepared by fluid bed granulation or by wet granulation, and improved methods of making these coated tablets.BACKGROUND OF THE INVENTION[0003]Protein kinases are important in the transmission of biochemical signals, which initiate cell replication. Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in adverse conditions including cancer [Traxl...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/48A61K31/4709A61P35/00
CPCA61K9/2027A61K9/2054A61K9/28A61K9/284A61K31/4709A61K9/2077A61P35/00A61P43/00
Inventor ASHRAF, MUHAMMADMAHMUD, MAINUDDINGOOLCHARRAN, CHIMANLALLGHOSH, KRISHNENDUNAGI, ARWINDER SINGH
Owner WYETH LLC
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